Isoflavones useful as anti-inflammatory agents
Antiinflammatory compositions and method of use
Use of flavone derivatives for gastroprotection
Method of treating topical angiogenesis-related disorders
Clear oil-containing pharmaceutical compositions
Protected forms of a combination of pharmacologically active agents and uses therefor
Methods of treating chronic inflammatory diseases using carbonyl trapping agents
Composition and method for treatment of inflammation and pain in mammals
Synergistic analgesic combination of oxycodone and rofecoxib
ApplicationNo. 09943048 filed on 08/30/2001
US Classes:514/406, Pyrazoles514/432, The hetero ring is six-membered514/413, Ring nitrogen is shared by the cyclos of the bicyclo ring system514/455, Chalcogen bonded directly to ring carbon of the hetero ring514/161, With heterocyclic compound514/456, Bicyclo ring system having the hetero ring as one of the cyclos (e.g., chromones, etc.)514/452, Plural ring oxygens in the hetero ring424/401, Cosmetic, antiperspirant, dentifrice424/451, Capsules (e.g., of gelatin, of chocolate, etc.)514/159, Ortho-hydroxybenzoic acid (i.e., salicyclic acid) or derivative DOAI424/464, Tablets, lozenges, or pills536/8, Flavon sugar compounds514/282, One of the five cyclos is five-membered and includes ring chalcogen (e.g., codeine, morphine, etc.)424/497, Containing solid synthetic polymers424/735, Containing or obtained from Prunus (e.g., prune, cherry, plum, apricot, peach, almonds, etc.)514/156Hetero ring containing
ExaminersPrimary: Kwon, Brian-Yong S.
Attorney, Agent or Firm
Foreign Patent References
International ClassesA61K 31/415
FIELD OF THE INVENTION
This invention relates to the combination of enteric-coated low dose aspirin, antioxidants (falvanoids or flavonoids), and COX2 inhibitors for inflammatory, cancer and thrombosis disorders.
BACKGROUND OF THE INVENTION
One of the most adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is their ulcerogenic activity on the gastrointestinal tract. Flavonoids are shown to possess anti-inflammatory efficacy without the ulcerogenic side effects (ParmarN S, Ghosh M N. In Proceedings of the 6th Hungarian Bioflavonoids Symposium. Farkas L., et al. (Ed.), Elsevier, Amsterdam 513-516, 1981). Examples of those flavanoids and flavonoids are as listed in the recent review (Lin J-K, Tsai S-H, Lin-ShiauS-Y. Drugs of the Future 26: 145-152; 2001). Flavanoids, flavonoids, and isoflavones are shown to be effective inhibitors of angiogenesis, tumor growth and tumor metastasis (Igura K, Ohta T, Kuroda Y, Kaji K. cancer Lett. 171:11-16; 2001; Kimura Y,Okuda H. J Nutr. 131: 1844-1849; 2001; Lin J-K, Tsai S-H, Lin-Shiau S-Y. Drugs of the Future 26: 145-152; 2001). The recent marketing of two selective cyclooxygenase 2 (COX-2) inhibitors climaxes the first phase of an exciting and fast-paced effort toexploit a novel molecular target for nonsteroidal anti-inflammatory drugs (NSAIDs). Much has been written in the lay and scientific press about the potential of COX-2 inhibitors as anti-inflammatory and analgesic agents that lack the gastrointestinalside-effects of traditional NSAIDs. Although research on COX-2 inhibitors has focussed mainly on inflammation and pain, experimental and epidemiological data suggest that COX-2 inhibitors could be used in the treatment or prevention of a broader rangeof diseases. Recent reports suggested increased thrombogenicity of COX2-specific inhibitors (Catella-Lawson F, Crofford L J, Am J Med 110: p28S-32S; 2001) in high risk patients suggesting the need for an adjunct antiplatelet agent.
Antiplatelet therapy has become a standard treatment of acute and chronic arterial thrombotic diseases. Among current available anti-platelet drugs, aspirin is the drug of choice for secondary prevention of myocardial infarction (Schror K.Antiplatelet drugs. Drugs 50:7-28, 1995). Its antiplatelet activity is mainly due to the irreversible inhibition of the platelet cyclo-oxygenase causing a last-lasting blockade of platelet-dependent thromboxane A2 formation. Sincepro-inflammatory stimuli might trigger the extension of thromboembolic disorders and vice versa, the combination of standard dose of COX2 inhibitors (anti-inflammatory) and aspirin (antiplatelet limited anti-inflammatory) at the 70-85 mg would improvethe efficacy and safety of each other. Additionally, COX2 inhibitors similar to the flavanoids exhibited anti-angiogenesis and anti-tumor efficacy. Recent studies demonstrated overexpression of COX-2 in multiple human tumors and pharmacologicalevidence in animal models, which indicate that COX-2 inhibitors could be used in the prevention or treatment of a broader range of disease (Kalgutkar A S, Zhao Z. Curr Drug Targets. 2(1): 79-106, 2001).
Compared with traditional non-steroidal anti-inflammatory drug agents, use of COX-2 selective inhibitors is associated with decreased incidence of adverse gastric events as a result of minimal inhibition of gastroprotective COX-1, but withequivalent anti-inflammatory benefit through inhibition of COX-2 . However, there is evidence to suggest that the `COX-1=constitutive, COX-2=inflammatory` paradigm is less distinct than originally proposed. Furthermore, selective COX-2 inhibitors mayhave other consequences as a result of the change in the eicosanoid profile. Thus, despite the relatively safe gastrointestinal profile, vigilant post-marketing surveillance for other adverse effects is required (Penglis P S, James M J, Cleland L G.,Intern Med J 2001;31(1):37-41). In that regard, recent clinical reports suggested increased thrombotic events in patients taking COX2 inhibitors suggesting the urgent need for the use of the COX1 inhibitory efficacy of aspirin to improve such seriousadverse outcome when using COX2 inhibitors for long term.
The recent marketing of two selective cyclooxygenase-2 (COX-2 ) inhibitors, celecoxib and rofecoxib is remarkable considering that COX-2 was only discovered eight years ago as a growth factor- and cytokine-inducible gene. Concomitant with thesepharmaceutical successes is the advances in our understanding of the molecular and structural basis for selective COX2 inhibition. In addition to the existing inhibitor classes, there are many novel structural classes which have recently emerged due toa better understanding of the active site differences between the two isozymes (Kalgutkar A S, Zhao Z., Curr Drug Targets 2001; 2(1): 79-106). In addition to its role in inflammation, recent studies suggest that COX-2 -derived prostaglandin may play apivotal part in the maintenance of tumor viability, growth, and metastasis. NSAID epidemiological evidence, studies demonstrating overexpression of COX-2 in multiple human tumors and pharmacological evidence in animal models, which indicate that COX-2inhibitors could be used for the prevention or treatment of a broader range of disease.
SUMMARY OF THE INVENTION
One object of the present invention is to provide a method of preventing thrombotic complications due the long-term use of COX2 inhibitors and to enhance its anti-inflammatory and anticancer efficacy by combining it with low dose enteric coatedaspirin and flavanoids. This combination therapy in a mammal comprising: administering to said mammal the combination in a therapeutically effective amount of (i) a COX2 inhibitors selected from the group consisting of celecoxib (CelebrexR),rofecoxib (VioxxR), and other specific COX2 inhibitors (ii) aspirin and (iii) antioxidants selected from the group consisting of flavanoids, flavonoids or isoflavones, wherein at least one of the COX2 inhibitors, at least one of the flavanoids andaspirin are used.
Another object of the present invention is to provide a method of treating inflammatory disorders, cancer and thrombosis in a mammal wherein the combination of (i) and (ii) or (iii) above are administered in amounts to provide a synergisticeffect in improving the efficacy and safety.
DETAILED DESCRIPTION OF THE INVENTION
The combinations of a COX2 inhibitors with aspirin and antioxidants useful in the treatment of inflammatory and thrombotic disorders including rheumatoid arthritis, atherosclerotic arterial disease, valvular heart disease, cerebrovascular diseasesuch as stroke, atrial fibrillation, coronary artery disease such as myocardial infarction and unstable angina, coronary artery bypass grafts, peripheral vascular disease, thromboembolic complications of prosthetic cardiovascular devices such heartvalves and vascular grafts. These combinations are also expected to be useful in combining with endovascular stenting procedures such as percutaneous transluminal coronary angioplasty, to prevent subsequent arterial thrombus formation and reocclusion. Also useful in the treatment of thrombosis is the combination in a therapeutically effective amount of tissue plasminogen activator and the GPIIb/IIIa antagonists. Specific examples of useful GPIIb/IIIa antagonist compounds are abciximab, eptifibatide,tirofiban, lamifiban, lefradafiban, sibrafiban (Ro-48-3657), orbofiban and xemilofiban described in the paper of Graul et al. and Scarborough (Graul A, Martel A M and Castaner J. Xemilifiban; Drugs of the Future 22: 508-517, 1997; Scarborough R M;Eptifibatide. Drugs of the Future 23: 585-590, 1998). Of these, lamifiban, lefradafiban, sibrafiban, orbofiban and xemilofiban are preferred. Others will be readily apparent to those skilled in the art.
"Therapeutically effective amount" is intended to include an amount of a combination of compounds claimed effective to treat inflammatory and thrombotic disorders in a mammal.
By "administered in combination", "combination", or "combined" when referring to compounds described herein, it is meant that the compounds or components are administered concurrently to the mammal being treated. When administered in combinationeach compound or component or component may be administered at the same time or sequentially in any order or at different points in time, so as to provide the desired therapeutic effect.
DOSAGE AND FORMULATION
Combinations of standard doses of COX2 inhibitors, aspirin at doses ranging from 70-350 mg, and antioxidants are administered as treatment for inflammatory, cancer, and thrombotic disorders. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95%by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also beadministered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose. starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets andcapsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from theatmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administrationpreferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers aredescribed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, a standard reference text in this field, the contents of which are incorporated herein by reference.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 0.1 to 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.
Soft Gelatin Capsules
A mixture of active ingredient in digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 0.1 to 100 mg of theactive ingredient. The capsules should then be washed and dried.
A large number of tablets can be prepared by conventional procedures so that the dosage unit is 0.1 to 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
An aqueous suspension can be prepared for oral administration so that each 5 ml contain 0.1 to 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and0.025 mg of vanillin.
The combined compounds of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, forexample, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it ispossible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oraladministration is desired provides for combined compounds wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physicalcontact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulationof combined compounds in which the one compound is coated with a sustained and/or enteric release polymer, and the other compound is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose or other appropriate materialsas known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric-coated compound and the other active ingredient are blended together and thencompressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebolayers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form ofa plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation ofthe other active ingredient.
These as well as other ways of minimizing contact between the combined compounds, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent tothose skilled in the art, based on the present disclosure.
Each therapeutic compound of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. For example, the compounds may be formulated together, in asingle dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. Alternatively, when not formulated together in a single dosage unit, an individual COX2 inhibitors may be administered at the sametime as either aspirin or antioxidants (flavanoids, flavonoids or isoflavones) or sequentially, in any order thereof.
As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode androute of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
The proper dosage of a COX2 inhibitor and low dose aspirin (35-150 mg) combination in an enteric coated formulation is the preferred form. By way of general guidance, typically a daily dosage may be about 0.01 milligram to about 1 gram of eachcomponent. By way of general guidance, when the compounds are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agentfor the treatment of thrombosis, in view of the synergistic effect of the combination.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise thanas specifically described herein.
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Field of SearchPyrazoles
The hetero ring is six-membered
Ring nitrogen is shared by the cyclos of the bicyclo ring system
Bicyclo ring system having the hetero ring as one of the cyclos (e.g., chromones, etc.)
Carboxy or salt thereof only attached indirectly to the benzene ring
Benzene ring nonionically bonded